Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin’s Lymphoma

Yttrium-90 (Y-90) ibritumomab
tiuxetan (Zevalin) radioimmunotherapy
was approved
by the US Food and Drug
Administration (FDA) in February
2002 and tositumomab/iodine-131
(I-131) tositumomab (Bexxar) was approved
by the FDA in June 2003 for
the treatment of patients with relapsed
or refractory low-grade, follicular, or
CD20-positive transformed B-cell
non-Hodgkin's lymphoma (NHL),
and rituximab (Rituxan)-refractory
follicular NHL. In this excellent
review, Drs. Ghobrial and Witzig
describe the rationale for radioimmunotherapy
and the relevant clinical
trials that formed the basis for
FDA approval.
The rationale for radioimmunotherapy
in lymphoma is compelling.[1]
Kaminski et al introduced I-131-labeled
anti-B1 antibody, a murine anti-
CD20 monoclonal antibody.[2] Press
studied tositumomab/I-131 tositumomab
with high-dose chemotherapy
and autologous stem cell transplant in
patients with recurrent lymphoma.[3]
Witzig et al reported on a multicenter
phase I/II trial of ibritumomab tiuxetan.[
4] The development of successful
yttrium-labeled radioimmunoconjugates
was dependent upon the chelation
chemistry developed by Quadri
et al, which allowed for stable binding
of the yttrium to the DPTA conjugate
by altering the 2- and 3-carbon
moieties, resulting in a urea bond.[5]
The high response rates reported by
Witzig and summarized in this review
are intriguing and provide proof
of principle for this novel therapy.
In studies reported to date, the overall
response rate to radioimmunotherapy
is > 80%, with complete response
rates between 20% and 30% for patients
with refractory NHL. Furthermore,
it is becoming apparent that a
significant minority of patients (about
20% to 25%) have durable remissions
that last longer than 5 years.[6] It remains
to be seen if any of these patients
are cured of their disease.
Late Toxicity
One of the anticipated difficulties
with radioimmunotherapy is late toxicity.
The toxicity seen in radioimmunotherapy
trials thus far has been
minimal, mostly hematologic and reversible.
Less than 2% of patients in
ibritumomab tiuxetan trials developed
a human antimurine antibody
(HAMA) or human antichimeric antibody
(HACA) response.[6] We believe
this low incidence of HAMA/
HACA is related to the use of chimeric
antibody for pretreatment, the
small dose of parent mouse antibody
(between 2 and 10 mg), and the extensive
prior therapy received by most
patients (with resulting immunosuppression).
Thus far, the incidence of secondary
malignancy, myelodysplastic syndrome,
or acute myeloid leukemia, is
estimated to be 1% to 2%.[7] A review
of the literature in patients who
have not undergone transplantation
but have had conventional-dose chemotherapy
for low-grade lymphoma
reveals that the rate of secondary malignancy
is between 4% and 8%, developing
over the course of 2 to
9 years after the initiation of treatment.[
8] We believe that second malignancies
may be a long-term
complication of lymphoma treatment
in general and not necessarily associated
with either rituximab or radioimmunotherapy.
However, it is
critical that these patients are followed
long-term.
Other late effects such as gonadal
toxicity need to be investigated. We
recently initiated a trial to prospectively
study the fertility of men and
women receiving ibritumomab tiuxetan
therapy.
Role of Radioimmunotherapy
Many other questions remain regarding
the efficacy of radioimmunotherapy.
For example, what is the
appropriate role and best integration
of radioimmunotherapy into bone
marrow transplant preparative regimens
and the activity of such treatment
in less common forms of NHL,
such as mantle cell lymphoma?
Radioimmunotherapy has been
studied in the setting of hematopoietic
transplantation for relapsed NHL.
Ibritumomab tiuxetan and tositumomab/
I-131 tositumomab have been examined
in phase I/II trials in
combination with standard autologous
transplant regimens (carmustine
[BCNU]/etoposide/cytarabine/melphalan
[Alkeran] and cyclophosphamide
[Cytoxan, Neosar]/etoposide)
and has proven to be feasible.[3,9]
Phase III trials need to be developed
to study the role of radioimmunother-
apy in autologous transplantation.
Furthermore, studies of radioimmunotherapy
with allogeneic transplantation
are needed, where the radioimmunoconjugate
is part of a preparative
regimen for patients with
lymphoma who are undergoing nonmyeloablative
therapy.
The early phase I/II data, which
suggested minimal activity in mantle
cell lymphoma,[4] might have been
influenced by the massive splenomegaly
seen in the first three patients
treated. These patients' spleens responded,
but their indicator lesions
did not, lending support to the "sink
phenomenon," whereby the bulk of
radioactivity concentrates at the bulkiest
sites of disease.
Conversely, very little information
exists regarding the biodistribution
of the radioisotope in patients with
minimal residual disease, as most
studies to date have only included
patients with measurable nodal disease.
This concept will be studied in
an Eastern Cooperative Oncology
Group study, which will investigate
the use of ibritumomab tiuxetan following
R-CHOP chemotherapy (rituximab
plus cyclophosphamide,
doxorubicin HCl, vincristine [Oncovin],
prednisone) in patients with
mantle cell lymphoma. This question
can also be investigated in stem cell
transplant studies where patients receive
radioimmunotherapy when the
disease burden is low.
Radiation Enhancement
There have been attempts to take
advantage of radiation sensitizers with
external-beam radiation, but to date
there have been no studies with radioimmunoconjugates.
We have been
interested in the redox-active agent
motexafin gadolinium (MGd), which
has shown activity when combined
with external-beam radiation in patients
with lung cancer and brain metastases.[
10] We have started a
phase I/II trial combining MGd with
ibritumomab tiuxetan for the treatment
of patients with relapsed/refractory
NHL. MGd is a tumor-selective
redox mediator that generates reactive
oxygen species such as hydrogen
peroxide[11] and enhances the
efficacy of ionizing radiation. Moreover,
MGd induces apoptosis in various
lymphoma cell lines and is additive
to rituximab.[Personal communication,
Richard Miller, Pharmacyclics, Inc]
Combination ibritumomab tiuxetan
(0.4 mCi/kg) and MGd (2.5 mg/kg)
therapy has been well tolerated by
the first cohort treated.
Therapeutic Combinations
Although there has been much debate
in the academic, private practice,
and pharmaceutical communities regarding
the relative merits of ibritumomab
tiuxetan and tositumomab/
I-131 tositumomab, investigators
should put marketing questions aside
and take advantage of the different
physical properties that characterize
Y-90 and I-131. Because the bulk of
the energy is distributed along a short
path with I-131 and a long path with
Y-90, the possibility of combined radioimmunotherapy
in NHL is not farfetched,
with ibritumomab tiuxetan
given for initial bulky disease and tositumomab/
I-131 tositumomab for minimal
residual disease. Clinical trials to
evaluate this strategy should be
planned.
The exact sequence of radioimmunotherapy
in the treatment algorithm
for low-grade lymphoma has
not yet been defined. Radioimmunotherapy
should have a major role as
second- or third-line therapy (depending
on sequencing with rituximab),
following monoclonal antibody and
alkylating agents, but prior to purine
analog-based treatment such as fludarabine.
Exposure to purine analogs
before ibritumomab tiuxetan will delay
blood count recovery and may
result in prolonged cytopenias.
Recent reports indicate that radioimmunotherapy
does not preclude
subsequent treatment for NHL.[12]
Chemotherapy and other NHL therapies
(including stem cell transplant
and immunotherapy) can be administered
following radioimmunotherapy.[
6,12] It is important that clinical
investigation of this novel modality
continues, to see if the early successes
can be duplicated and to better assess
the role of radioimmunotherapy
in the treatment of lymphoma.

Disclosures

Dr. Gordon receives
clinical trials research support from Biogen
Idec.